Radiation-induced liver disease: current understanding and future perspectives

Abstract

Although radiotherapy (RT) is used for the treatment of cancers, including liver cancer, radiation-induced liver disease (RILD) has emerged as a major limitation of RT. Radiation-induced toxicities in nontumorous liver tissues are associated with the development of numerous symptoms that may limit the course of therapy or have serious chronic side effects, including late fibrosis. Although the clinical characteristics of RILD patients have been relatively well described, the understanding of RILD pathogenesis has been hampered by a lack of reliable animal models for RILD. Despite efforts to develop suitable experimental animal models for RILD, current animal models rarely present hepatic veno-occlusive disease, the pathological hallmark of human RILD patients, resulting in highly variable results in RILD-related studies. Therefore, we introduce the concept and clinical characteristics of RILD and propose a feasible explanation for RILD pathogenesis. In addition, currently available animal models of RILD are reviewed, focusing on similarities with human RILD and clues to understanding the mechanisms of RILD progression. Based on these findings from RILD research, we present potential therapeutic strategies for RILD and prospects for future RILD studies. Therefore, this review helps broaden our understanding for developing effective treatment strategies for RILD.

Figure 1

Simplified model of liver-specific cellular events in radiation-induced liver injury. (a) In the normal liver, liver sinusoids are lined with SECs and KCs. Quiescent hepatic stellate cells (qHSCs) are located in the space of Disse and are in close contact with HCs and SECs. (b) In the irradiated liver, ① injured SECs undergo apoptosis and release TNF-α, which promotes HC apoptosis and KC activation. ② In addition, injured SECs induce the penetration of red blood cells (RBCs) and activate fibrin deposition in central veins (CVs), leading to sinusoidal obstruction. ③ The ensuing hypoxic environment leads to the death of HCs and the activation of KCs. ④ Activated KCs release TGF-β, the major profibrogenic cytokine, which promotes the transdifferentiation of qHSCs into MF-HSCs. ⑤ Apoptotic HCs produce Hh ligands, which trigger the proliferation of Hh-responsive cells, such as HSCs. MF-HSCs accumulate and promote the deposition of extracellular matrix proteins, leading to liver fibrosis in the late stage of RILD.